Perinatal exposures may lead to increased risk of childhood cancers, as well as those later in life. Preconceptional parental, transplacental, and/or neonatal exposures may be involved. Studies with animal models are utilized to increase understanding of underlying cellular and molecular mechanisms. A possible mechanism of paternal effects on childhood cancer is male-mediated transgenerational carcinogenesis. Exposure of male mice to chromium(III), an environmental/occupational metal, results in increased neoplasms and other lesions in the offspring. The nature of these changes suggested hormonal involvement, and we have discovered alterations in serum glucose, corticosterone, IGF1, and the thyroid hormone T3. It is also important to discover the molecular mechanism in the sperm, by which changes-in-gene-expression signals are passed to offspring. Use of representational difference analysis, bisulfite sequencing, and pyrosequencing has revealed hypomethylation in the spacer-promoter region of the ribosomal RNA gene in sperm from Cr(III)-treated males. Ribosomal RNA is implicated in both growth and cancer. In lung tissues of offspring, gene methylation is decreased, and ribosomal RNA increased. Further detailed characterization is in progress, as well as work with cultured mouse and human lung cells is allowing molecular manipulation and controlled endpoint analysis. New results implicate small nuclear RNAs in regulation of the rRNA gene in human lung cancer cells. Effects on offspring glucose, hormones, and body weights suggested that the Cr(III) effects could be related to energy metabolism. Therefore another protocol has been tried, involving limited diet restriction of fathers (24 hr fasting). Remarkably, this treatment 2 weeks before mating results in a highly significant reduction in average serum glucose in both male and female offspring. Alterations in offspring corticosterone, IGF1, and body weight are also noted though more variably. These results suggest that physiological transgenerational effects may be common and have implications for many widespread diseases in addition to cancer.